E m e r g i n g Tre n d s

in Diagnosis and
Tre a t m e n t o f
Rheumatoid Arthritis
James T. Birch Jr,

MD, MSPH*,

Shelley Bhattacharya,

DO, MPH

KEYWORDS
 Rheumatoid arthritis  Juvenile rheumatoid arthritis
 Disease-modifying antirheumatic drugs  Synovitis
 Elderly onset rheumatoid arthritis

EPIDEMIOLOGY

Rheumatoid arthritis (RA) is a chronic inflammatory disease with multiple comorbidities and is a cause of disability for many children and adults worldwide. The role of
primary care is essential in early diagnosis and treatment of this debilitating disease.
The prevalence of RA is estimated to be 0.8% globally, with women 2 to 4 times as
likely as men to develop the disease. The incidence of RA in the United States is estimated at 25 per 100,000 men and 54 per 100,000 women, affecting approximately 2.1
million people.1,2 Age at onset is usually between 30 and 50 years of age; however,
juvenile RA and elderly onset RA (over age 65) also occur.1,2
In the United States, arthritis and other rheumatic conditions are the leading cause
of disability. Approximately 39% of adults with arthritis report limitations in their physical activities because of their condition. Patients with RA are more than 7 times as
likely to have greater than moderate disability as their sex- or age-matched counterparts. In addition, RA disability is linked with increased mortality. The Health Assessment Questionnaire (HAQ) disability index used to follow RA patients found that
a change of 1 standard deviation in the HAQ correlates to an odds ratio for mortality
of 2.3.2 After 10 to 20 years of having the disease, as many as 80% show a compromise of their activities of daily living. Beginning early treatment can reduce the potential for disability by more than 60%.3
In economic terms, RA accounts for an estimated 250,000 hospitalizations and 9
million physician office visits annually. Within 2 to 3 years of diagnosis, 20% to 30%

The investigators have nothing to disclose.

University of Kansas School of Medicine, Department of Family Medicine, Division of Geriatric
Medicine & Palliative Care, 3901 Rainbow Boulevard, MS-1005, Kansas City, KS 66160-0001, USA
* Corresponding author.
E-mail address: jbirch@kumc.edu
Prim Care Clin Office Pract 37 (2010) 779792
doi:10.1016/j.pop.2010.07.001
primarycare.theclinics.com
0095-4543/10/$ see front matter 2010 Elsevier Inc. All rights reserved.

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of those with RA become permanently disabled from work because of pain, impaired
physical function, and transportation difficulties.1,2 The total costs of arthritis and other
rheumatologic conditions in the United States in 2003 was $128 billion ($80.8 billion
from direct medical costs and $47 billion from indirect costs such as lost earnings).
In addition, a reduced life expectancy of 5 to 15 years can occur.3
RISK FACTORS

Several environmental and genetic factors that potentially contribute to increased risk
of developing RA have been identified. There are no definitive risk factors.
Environmental factors include hormonal exposure, tobacco use, microbial exposure, smoking, and consumption of more than 3 cups of decaffeinated coffee daily.1,4
Among these, tobacco use has the most consistent evidence for an association.4
Genetic factors include female gender, positive family history, older age, and the
HLA genotype.1,4 In monozygotic twins, the concordance rate for the development
of RA is more than 30%.1 Siblings of patients with the disease are 2 to 4 times
more likely to develop the disease than persons who are not related.3 Among whites
who have RA, 80% express the HLA-DR1 or HLA-DR4 subtypes.1
Risk of RA is reduced through high vitamin D intake, tea consumption, use of oral
contraceptives, and with breast-feeding.1 Women who have never given birth seem
to have a slight to moderate risk of developing RA, and the evidence is mixed
regarding an association between RA and hormone replacement therapy.1
PATHOPHYSIOLOGY

The pathophysiology of RA essentially remains only partially understood. A complicated interaction between environmental and genetic factors eventually results in
the onset of disease. A viral infection or other biologic factor can initiate an abnormal
autoimmune inflammatory response in persons who are genetically predisposed to
RA. Where chronic inflammation exists in these cases of RA, there is an imbalance
among the mediators controlling the systems response, resulting in eventual damage
to cartilage and bone.5 The pathophysiology of RA originates with inflammation of
the synovium at any joint location, possibly triggered by the presentation of an antigen,
autoantigen, or athrogenic peptide to the immune system. It appears that the subsequent cascade of inflammatory responses leads to proliferation of synovial macrophages, fibroblasts, and chondrocytes in the articular cartilage. These cells secrete
enzymes that degrade proteoglycans and collagen, which eventually precipitate synovial tissue destruction.5 Further infiltration by lymphocytes and other inflammatory
cells occurs and is accompanied by angiogenesis in the synovium, causing irregular
regrowth of the synovial tissue and eventually forming invasive pannus tissue. This
process stimulates the increased activity of osteoclasts, resulting in further inflammation, leading to more cartilage destruction and the characteristic bony erosion of RA
(Fig. 1).1 Continued ongoing release of inflammatory mediators along with interleukins,
tumor necrosis factor a (TNFa), cytokines, and proteinases, also contributes to the
development of systemic symptoms and the extra-articular manifestations of RA.1,5
There is suspected to be a shared epitope, possibly derived from the disease-associated HLA-DR4/1 allele that is initially presented by an antigen-presenting cell to the T
cell as a self-antigen.6 Later in life, these T cells could be activated by cross-reactive
antigens that display the shared epitope, leading to the inflammatory cascade.6
Multiple infectious agents are known to possess potentially cross-reactive peptides
so that possible reactivation of RA by these common and ubiquitous organisms might
occur.6

Diagnosis and Treatment of Rheumatoid Arthritis

Fig. 1. Pathogenesis of RA. (Reprinted from Pope RM. Apoptosis as a therapeutic tool in
rheumatoid arthritis. Nat Rev Immunol 2002;2(7):52735; with permission from Nature
Publishing Group.)

Research continues to elucidate the role of macrophages and their cytokines in

the synovitis of RA and to decipher the mechanisms of the apparent autonomous
and aggressive behavior of fibroblast-like synoviocytes.6 Greater understanding of
these elusive issues could have a significant impact on the therapeutic approach
to RA.

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DIAGNOSIS

No single test confirms the diagnosis of RA. Diagnosis is largely based on clinical findings and patient history, which is challenging because the symptoms are similar to
many other potential causes of joint inflammation and pain.3 There are several tests
that can be used to increase diagnostic probability and monitor disease progression.
It is imperative that a diagnosis be established as early as possible, because a delay as
much as 4 to 6 months in initiation of treatment could result in long-term joint injury.5
In 1987, the American College of Rheumatology (ACR), in conjunction with the
American Rheumatism Association, established 7 diagnostic criteria to aid in the clinical diagnosis of RA.5 These criteria are also used to define RA in epidemiologic
studies.4 Any patient who presents with at least 4 of the listed criteria for 6 weeks
or longer is considered to have RA (Table 1).7 Early RA is the classification of disease
that is diagnosed within 6 months of symptom onset. There is considerable focus in
this area because early treatment has been demonstrated to have a positive impact
on disease progression and prognosis.4
Efficient diagnosis of RA requires vigilant attention to the patients medical history.3
Signs of early synovitis in the absence of obvious joint deformity might be uncovered
by the squeeze test of the metacarpophalangeal (MCP) joints or the metatarsophalangeal (MTP) joints.3 A key sign of RA at the time of the onset is symmetric joint swelling
Table 1
1987 Criteria for the classification of acute arthritis of RA
Criterion

Definition

Morning stiffness

Morning stiffness in and around the joints, lasting at least 1 h

before maximal improvement

Arthritis of 3 or more
joint areas

At least 3 joint areas simultaneously have had soft tissue swelling

or fluid (not bony overgrowth alone) observed by a physician.
The 14 possible areas are right or left PIP, MCP, wrist, elbow,
knee, ankle, and MTP joints

Arthritis of hand joints

At least 1 area swollen (as defined above) in a wrist, MCP, or PIP

joint

Symmetric arthritis

Simultaneous involvement of the same joint areas (as defined in 2)

on both sides of the body (bilateral involvement of PIPs, MCPs,
or MTPs is acceptable without absolute symmetry)

Rheumatoid nodules

Subcutaneous nodules, over bony prominences, or extensor

surfaces, or in juxta-articular regions, observed by a physician

Serum RF

Demonstration of abnormal amounts of serum RF by any method

for which the result has been positive in <5% of normal control
subjects

Radiographic changes

Radiographic changes typical of RA on posteroanterior hand and

wrist radiographs, which must include erosions or unequivocal
bony decalcification localized in or most marked adjacent to the
involved joints (osteoarthritis changes alone do not qualify)

For classification purposes, a patient shall be said to have RA if he or she has satisfied at least 4 or
these 7 criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with 2
clinical diagnoses are not excluded. Designation as classic, definite, or probable RA is not to be
made.
Abbreviations: MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal; RF, rheumatoid factor.
Adapted form Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association
1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1998;31(3):31524;
with permission.

Diagnosis and Treatment of Rheumatoid Arthritis

with local heat and erythema. In the early phase there is usually no clinical evidence of
joint disease and no evidence of cartilage or bone loss on plain radiographs. The
physician or diagnostic clinician also needs to evaluate the patient for extra-articular
features of RA, which will determine the potential course of the disease and guide
treatment options.3

SYMPTOMS

Patients with RA typically present with pain and stiffness in multiple joints. However,
one-third of patients have initial symptoms at a solitary location. The most common
presentation of RA is that of an insidious onset of morning stiffness or diffuse aching
that lasts for at least 1 hour or longer, followed by involvement of the small peripheral
joints such as the MCP, MTP, and proximal interphalangeal (PIP).3 It is not unusual for
the larger joints to be affected first. Symptoms usually occur over weeks to months,
yet in 15% of patients onset can occur more rapidly over days to weeks. Most patients
have accompanying prodromal symptoms of weakness, fatigue, or anorexia. In 8% to
15% of patients, symptoms begin soon after a trigger event, such as a viral illness.1
Characterizing the pain often helps distinguish RA from other forms of arthritis, as
does a positive family history for RA. Determination of disability and ability to perform
activities of daily living facilitates monitoring the effects of treatment.
The joints that are usually affected are those with the highest ratio of synovium to
articular cartilage, such as the wrist, PIP, and MCP joints. The distal interphalangeal
and sacroiliac joints are usually not affected. Affected joints are usually warm, tender
to palpation, and boggy. There might be increased blood flow to the inflamed area with
subsequent symptoms of puffy hands by patients.1 Joint swelling is usually symmetric
and, with tenderness on palpation, is one of the key signs of RA.2 Beyond the joints,
axillary, cervical, or epitrochlear lymphadenopathy may be noted. Muscles in close
proximity to the inflamed joints often atrophy. Weakness is commonly out of proportion to the pain on examination. Joints are often held in flexion by patients to minimize
painful distension of the joint capsules. Clinically, one may also appreciate decreased
grip strength from tendon damage, tendon rupture in the wrist and fingers, decreased
range of motion in the shoulders from synovitis and anterior effusions, and heel pain
with antalgia from talus involvement. The hip is usually affected later, and hip involvement is usually rare.3

LABORATORY TESTS

Indications for testing include a history of persistent joint pain with early morning stiffness. Baseline laboratory tests are recommended and include a complete blood cell
count with differential, rheumatoid factor (RF), and erythrocyte sedimentation rate
(ESR) greater than 30 mm/h or C-reactive protein (CRP) greater than 0.7 pg/mL. Renal
and hepatic function parameters are also recommended because findings guide
medication choices, and monitoring should continue throughout the course of
treatment.1
RF is an immune complex consisting of an autoantibody and IgG. A positive RF is
not diagnostic of RA. Incidence of positivity increases with duration of disease (ie,
612 months), and with age. Of patients with RA, 20% may never have a positive
RF, approximately 5% to 10% of healthy individuals are RF positive, and RF might
also be positive in many other disease processes.1,8
Other laboratory tests that aid in the diagnosis of RA are as follows.

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Anticyclic Citrullinated Peptide IgG Antibody

When positive, this test supports the diagnosis of RA. It is produced in the first stage of
RA pathogenesis at the site of joint inflammation. During this process, citrullination of
synovial antigens occurs, involving several synovial proteins. The antibody, anticyclic
citrullinated peptide (anti-CCP), is secreted by B cells, which are present in the synovium and bone marrow of anti-CCPpositive patients.9 Anti-CCP is more than 98%
specific, and sensitivity increases when used in combination with RF. It might be negative during the course of early disease. One study found the anti-CCP antibody to be
associated with some parameters of disease activity and severity, being more specific
in patients with advanced RA with a mean duration of 9.8 years.10
Arthrocentesis (Joint Aspiration)

This option is a useful one if the diagnosis is uncertain. Arthrocentesis helps to differentiate crystal-induced arthropathies and septic arthritis. In RA, fluid is usually strawcolored, and fibrin flecks are often seen; clotting may occur at room temperature;
a white blood cell count of 5 to 25,000 per mm3 is common, with a differential count
of 85% polymorphonuclear leukocytes. Findings also include no crystals, low glucose
levels, and negative cultures.1,8 Synovial fluid evaluation for anti-CCP has been suggested by a study to be a useful tool to assist with diagnosis of RA in cases of undifferentiated arthritis. The presence of anti-CCP in synovial fluid is a high risk factor for
progression to RA.9 Some patients may have negative serum levels when the joint fluid
is positive.9
Plain Film Radiography

Plain film radiography remains the preferred method for initial examination to evaluate
bone and soft tissue changes. Although a definite diagnosis might not be possible,
even subtle findings and evaluation of soft tissue changes can facilitate a differential
diagnosis. Depending on the severity of the disease, radiography can reveal soft tissue
swelling and joint space narrowing as a consequence of cartilage thinning, or joint
space widening as an indication of joint effusion. Juxta-articular osteoporosis is
also one of the nonspecific changes that can confirm the clinical impression of an
inflammatory process.11
EXTRA-ARTICULAR SIGNS AND SYMPTOMS

Although well described, the prevalence and incidence of many extra-articular

features of RA are not accurately known.11 It is also difficult to separate these findings
into those that arise as a complication of the disease, its treatment, or an immunologic
disease associated with RA but occurring in isolation.11 Pathogenesis of extra-articular signs varies between patients and anatomic location of the findings, but it is
reasonable to conclude that any component in the autoimmune pathogenesis of RA
is associated. Extra-articular disease has a significant influence on mortality from
RA.11 Infection is the leading cause of death (25%), followed by cardiac and pulmonary disease (18%), with renal and gastrointestinal disease being equal but lower in
frequency (10%).11 Other manifestations of extra-articular disease are outlined in
Box 1.
JUVENILE RA

Children are not exempt from the disease of RA. The true incidence is unknown.12 A
2007 study by the Centers for Disease Control and Prevention estimates that

Diagnosis and Treatment of Rheumatoid Arthritis

Box 1
Extra-articular manifestations of RA
Rheumatoid nodules of varying size and consistency are found in up to 25% of patients.
Location: extensor area of the forearm (common), internal organs (rare). Complications:
gangrene and ulcer formation.
Hematologic: normocytic, normochromic anemia; thrombocytosis or thrombocytopenia;
lymphadenopathy.
Felty syndrome: the association of RA with leukopenia and splenomegaly
Vasculitis: may involve eyes, brain, skin, renal, cardiovascular, and gastrointestinal (GI) tract
Pulmonary: pleural effusions, pulmonary nodules, interstitial lung disease, bronchiolitis
obliterans with organizing pneumonia; complications of treatment with disease-modifying
antirheumatic drugs (DMARDs)
Cardiac: pericardial effusions; valvular lesions; cardiac manifestations from systemic influences
of RA such as serositis, amyloidosis, vasculitis, conduction abnormalities secondary to nodule
formation
Renal: microalbuminuria (correlates with disease activity); mesangial glomerulonephritis;
(nephritic syndrome); nephrotoxicity secondary to DMARDs
Ophthalmologic: keratoconjunctivitis sicca or secondary Sjogren syndrome; episcleritis and
scleritis (prompt treatment necessary to avert vision loss); effect of drug therapyrisk of
retinopathy with hydroxychloroquine requires ongoing surveillance
Neurologic: mononeuritis multiplex and central nervous system features including seizures,
aseptic meningitis, and stroke secondary to vasculitis. Entrapment neuropathies via nerve
impingement associated with subluxation of the atlantoaxial joint, amyloid deposits, or
nodules
Musculoskeletal: osteoporosis and fractures caused by disease process and corticosteroid
treatment. Muscular weakness of varying etiology
Amyloidosis: found in 21% of patients in postmortem studies of patients with RA
Data from Firestein GS, Panayi GS, Wollheim FA. Rheumatoid arthritis: frontiers in pathogenesis
and treatment. New York: Oxford University Press; 2000.

294,000 children in the United States younger than of 18 years (1 in 250) have been
diagnosed with arthritis or another rheumatologic condition.13 The most common
form of childhood arthritis is juvenile rheumatoid arthritis (JRA).13 The American Rheumatism Association acknowledges 3 clinical classifications of JRA: systemic-onset
disease (10%20%), polyarticular disease (20%40%), and pauciarticular disease
(30%40%).12 Clinical symptoms are varied in each category and each type has its
own unique presentation, clinical course, and immunogenetic association. The
polyarticular and pauciarticular forms contain more than 1 subgroup (Polyarticular:
RF-negative and RF-positive disease; Pauciarticular: early childhood onset and late
childhood onset).12 Recognition of the subgroups is important for the appropriate
diagnosis and treatment of the younger JRA patient.12 One feature that all JRA
patients have in common is the presence of chronic synovitis.
Once treatment is initiated, children should be encouraged to lead full lives as much
as possible. Occasionally, some may be disabled or too ill to be self-sufficient and
require inpatient rehabilitation. Support and counseling is necessary to prevent educational deficits, provide support of career plans, and in general to prevent children from
thinking of themselves as people with disability.12

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Currently 75% to 80% of children with JRA are expected to survive the disease
without disability.12 Those at greatest risk for joint destruction are those with
systemic-onset JRA and RF-positive polyarthritis. Careful follow-up is necessary for
all JRA patients throughout the course of active disease, and there is always the possibility of unexpected recurrences even after years of remission.12 However, the future
remains positive for most affected children.
ELDERLY ONSET RA

Elderly onset rheumatoid arthritis (EORA) includes patients who develop RA between
the age of 60 and 65 years. The prevalence is approximately 2% in this age group.14
Symptoms of EORA are different from those in younger patients, and 3 subsets have
been identified14:
1. Patients who have classic RA signs and symptoms with clinical onset similar to that
in patients who develop seropositive RA at an earlier age. These patients have high
levels of disease activity, and aggressive treatment is required.14
2. Patients presenting with symmetric arthritis associated with Sjogren syndrome.
The synovitis is less severe and more readily controlled than in the first subset.14
3. Patients have a clinical picture that mimics polymyalgia rheumatica. RF is negative
in the vast majority of cases but high levels of acute phase reactants are present.
Arthritis in this subset of patients is usually well controlled with low-dose corticosteroid treatment; joint damage and radiological changes are less severe than in the
other forms.14
EORA occurs in a balanced female to male ratio of about 1.5:1 to 2:1.14 Poorer functional outcomes have been noted in patients who score high on the HAQ and who have
RF seropositivity.14 However, overall, EORA patients are more likely to experience
clinical remission (odds ratio [OR] 5 2.99) with a much higher remission rate in the
seronegative EORA group than all other groups (including the younger seronegative
RA group). It should also be noted that continuous use of corticosteroids for more
than 3 months in EORA patients has been associated with joint erosion (OR 5 4.09).
Diagnosis of EORA requires early and appropriate initiation of DMARD therapy no
different from that given to younger RA patients. The higher remission rate in seronegative EORA patients implies that therapy might be given for a shorter duration than for
seropositive patients. Awareness should be heightened regarding the increased risk of
adverse events associated with RA treatments in the elderly patient. Careful follow-up
and prudent use of the appropriate medications is extremely important.14
DIFFERENTIAL DIAGNOSIS

The differential diagnosis of RA is extensive. Most patients present with symptoms in

common with RA. A careful clinical history, followed by a meticulous physical examination, and acquisition of prudent laboratory and imaging studies is mandatory to
initiate the diagnostic process.14 Differential diagnoses include but are not limited to
the conditions listed in Table 2.1,8,14 Potential causes of infectious arthritis include
hepatitis B and C, human immunodeficiency virus, and other bacterial infections.
Included in the differential diagnosis for EORA is remitting seronegative symmetric
synovitis with pitting edema syndrome (also known as RS3PE syndrome).14 This
condition historically develops abruptly in elderly patients with the finding of edematous symmetric arthritis involving the distal extremities, specifically hands and wrists
and/or feet and ankles. The edema on the dorsal aspect of the involved areas is

Diagnosis and Treatment of Rheumatoid Arthritis

Table 2
Differential diagnosis of RA
Connective tissue diseases
Fibromyalgia
Other forms of arthritis (infectious, reactive,
viral, osteoarthritis)
Seronegative spondyloarthropathies
Sarcoidosis
Hemochromatosis
Infectious carditis

Crystalline arthropathy (polyarticular gout,

pseudogout, chronic calcium
pyrophosphate arthropathy)
Acute rheumatic fever
Thyroid disease
Still disease
Polymyalgia rheumatica
Malignancy-related arthritis
Hypertrophic osteoarthropathy

caused by extensor tenosynovitis. There is no development of bony erosions and RF is

negative. Patients with the condition demonstrate a satisfactory response to corticosteroids, and the prognosis is excellent. It is still debatable as to whether this
syndrome is part of the spectrum of RA or a completely different medical condition.
Many of the same findings can occur in patients with polymyalgia rheumatica, other
inflammatory arthropathies, and malignancies involving the hematologic system as
well as solid tumors.14

TREATMENT

Early treatment reduces the rate of disease progression and is therefore recommended to be initiated during the early phase of the disease.1 Many patients experience
RA symptoms for an average of 9 to 12 months before a diagnosis is made.2 The
American College of Rheumatology Subcommittee on Rheumatoid Arthritis (ACRSRA)
recommends that patients with suspected RA be referred to a rheumatologist within 3
months of presentation to confirm the diagnosis and initiate treatment. The National
Guideline Clearinghouse also supports specialist referral and recommends urgent
referral if the small joints of the hands or feet are affected, more than 1 joint is affected,
or there has been a delay of 3 months or more between the onset of symptoms and
seeking of medical advice.15 Therapeutic goals must be discussed with the patient
and should include preservation of quality of life, reducing pain, minimizing inflammation, protecting the joints, and reducing RA complications.1
Patients with mild disease and normal radiograph joint findings can begin treatment
with hydroxychloroquine, sulfasalazine, minocycline, or methotrexate.1,16 Fig. 2
contains an algorithm that simplifies the approach to treatment.1 Nonsteroidal antiinflammatory drugs (NSAIDs) should not be used alone, as they do not change the
disease course. Precautions should be observed with NSAID use, as RA patients
are almost twice as likely as osteoarthritis patients to have serious complications
from NSAID use.
Cyclooxygenase-2 (COX-2) selective NSAIDs are equally as effective as nonselective NSAIDs for reducing pain and inflammation as well as improving joint function.
These agents should be used with caution in renal and geriatric patients.1 There is
also ongoing concern of the cardiovascular safety of COX-2 NSAIDs. Therefore, careful patient selection is imperative. There have been long-term studies, such as the
CLASS study (Celecoxib Long-term Arthritis Safety Study), which showed a reduction
in adverse upper GI events in patients taking celecoxib alone without low-dose aspirin
versus NSAIDs alone or COX-1 versus COX-2 NSAIDs with low-dose aspirin.17 Owing
to the cardiac benefit of low-dose aspirin for patients with moderate or high

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Diagnosed rheumatoid arthritis

In anticipation of possible future biologic therapy;

Check tuberculosis and candida control skin tests
before placing on steroids or other DMARDs.
Baseline chest radiograph

Erosions visible on radiograph?

Yes

No
Mild disease

Moderate or severe disease

Trial of hydroxychloroquine (Plaquenil), sulfasalazine

(Azulfidine), or minocycline (Minocin)

Adequate control of joint pain and swelling?

No
Yes

Trial of methotrexate, 10 to 15 mg once per

week hydroxychloroquine sulfasalazine

Adequate control of joint pain and swelling?

Yes
No
Increase dosage of methotrexate to
20 mg orally once per week; at
25 mg, switch to SC or IM.

Adequate control of joint pain and swelling?

Yes
No
Monitor disease activity every three to six months.
Annual radiographs

Switch from methotrexate to leflunomide

(Arava) or azathioprine (Imuran);
or add leflunomide or azathioprine to
b
methotrexate ;
b
or add a biologic agent to methotrexate.

Fig. 2. Treatment algorithm for RA. aThe following laboratory tests should be performed
before methotrexate therapy begins, every 2 weeks for 6 weeks, then, if normal, every 2
months: complete blood count with differential, platelets, aspartate transaminase levels,
albumin levels, and creatinine levels. When starting methotrexate add 1 mg oral folic
acid per day to decrease side effects, and caution the patient to avoid alcohol. bWhen adding another DMARD to methotrexate, decrease the dosage of methotrexate to 10 to 15 mg
once per week. (Reprinted from Rindfleisch JA, D Muller. Diagnosis and management of
rheumatoid arthritis. Am Fam Physician 2005;72(6):1042; with permission.)

cardiovascular risk (Framingham scores >10%), a reasonable and proven strategy is

to use a nonselective NSAID in combination with misoprostol or a proton pump inhibitor, instead of celecoxib, for patients on low-dose aspirin therapy who are at high risk
for gastropathy.18
Glucocorticoids at dosages of less than 10 mg of prednisone daily are also highly
effective to treat RA pain and stiffness, and can slow joint damage. Because of the
multiple adverse effects of steroid use, dosages should be kept to the lowest needed

Diagnosis and Treatment of Rheumatoid Arthritis

to achieve therapeutic benefit. When discontinuing glucocorticoid therapy, a slow

taper is recommended over approximately 1 month.1 In addition, recent guidelines
by the American Association of Clinical Endocrinology recommend supplements of
1500 mg of calcium and 800 IU of Vitamin D3 daily for patients receiving glucocorticoid
therapy and bisphosphonate therapy for all adult women requiring more than 7.5 mg of
prednisone or its equivalent for over 3 weeks.19 When a single joint contributes to
disability, intra-articular glucocorticoids are a safe, yet temporary option. Intra-articular injections can also be used as bridge therapy until DMARDs become effective,
which has the potential to take several months.5 Infectious causes should be ruled
out before administering an injection.1
The recently published 2008 ACR guidelines for management of RA recommend
using disease duration as a guide for treatment. There are 3 categories of disease
duration: less than 6 months (considered to be equivalent to early disease), 6 to 24
months (considered to be equivalent to intermediate disease duration), and more
than 24 months (considered to be long or longer disease duration). For biologic therapies, early disease is further subdivided by disease duration of less than 3 months or
3 to 6 months, when disease activity is high.16 Most RA treatment plans include an
NSAID for pain control with careful use of oral or intra-articular glucocorticoids and
the initiation of a DMARD. Unlike past regimens, the ACR now recommends that
DMARDs be initiated early in the disease to reduce progression.16 Treatment protocols have been modified as a result of research demonstrating that joint damage
begins early in RA, DMARDs have significant benefits when begun early, DMARD
benefits are enhanced when used in combination, and new DMARDs are available
with good therapeutic benefits.
The nonbiologic DMARDs addressed in the 2008 ACR recommendations are hydroxychloroquine, leflunomide, methotrexate, minocycline, and sulfasalazine. The biologic
DMARDs included are abatacept, adalimumab, etanercept, infliximab, and rituximab.
The remaining DMARDs are not included because they were not subjected to a systematic review of the literature due to their infrequent use (<5% of RA patients, eg, anakinra)
and/or the high incidence of adverse events when they are used (cyclophosphamide,
D-penicillamine, staphylococcal immunoabsorption column, tacrolimus). Abatacept
and rituximab are the only 2 DMARDs that received an evidence-based recommendation (Level of Evidence for use: A). Disease activity (low, moderate, or high) and
prognostic features are included with disease duration in evidence-based recommendations. Prognosis was defined as poor if patients had active disease with multiple
tender, swollen joints, elevated RF, elevated anti-CCP antibodies, elevated ESR or
CRP, and evidence of radiographic erosions.16 Important predictors for a worse
outcome include the presence of any of the aforementioned risk factors and poor
physical functioning.16
DMARDs should be considered for all RA patients, regardless of stage. The DMARD
agent of choice depends on age, compliance, disease severity, physician comfort,
and comorbidities. Increasing evidence shows that DMARD combinations can be
more effective than single regimens. Regarding the nonbiologic DMARDs, the ACR
recommends the initiation of methotrexate or leflunomide therapy for patients with
all disease durations and all degrees of disease activity. Hydroxychloroquine or minocycline monotherapy is recommended for patients without poor prognostic features,
with low disease activity and with disease duration of less than 24 months. Sulfasalazine monotherapy is recommended for patients with all disease durations without poor
prognostic features and with all degrees of disease activity.16
Those with radiographic joint findings and more severe disease should begin dual
nonbiologic DMARD combination therapy. Methotrexate plus hydroxychloroquine is

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recommended for patients with moderate to high disease activity, regardless of duration or presence of poor prognostic features. Methotrexate plus sulfasalazine is recommended in patients with all durations if they have high disease activity and poor
prognostic features. Hydroxychloroquine plus sulfasalazine is recommended only in
patients with 6 to 24 months of disease duration and with high disease activity yet
without poor prognostic features.16
Triple DMARD combination therapy of sulfasalazine plus hydroxychloroquine plus
methotrexate is recommended for all patients with poor prognostic features and
moderate to high levels of disease activity, regardless of duration of disease.
Regarding biologic DMARDs (anti-TNFa agents), the ACR recommendations are
divided into those with RA for lass than 6 months and those with RA for longer than
6 months. The anti-TNFa agents are efficacious in improving disease activity, function,
and quality of life when used alone or in combination with methotrexate or other nonbiologic DMARDs. Recommendations for the use of anti-TNFa agents with methotrexate are limited only to patients with early RA who have never received DMARDs,
have had high disease activity for lass than 3 months, a poor prognosis, and without
cost restrictions. In those with longer RA duration, the ACR recommends the use of
anti-TNFa agents in patients for whom methotrexate monotherapy or combination
therapy with nonbiologic DMARDs was inadequate.16
The risk of death from infection in patients with RA is approximately 6 to 9 times
greater than in non-RA populations.20 Risk factors for infections include corticosteroid
therapy, comorbidities, skin breakdown, joint surgery, and established RA. Nonbiologic and biologic DMARDs and TNF antagonists may place patients at greater risk
of infection. Therefore, when a fever presents in an RA patient, sepsis should be
strongly considered and a rheumatologist should be consulted early during the initiation of care. However, patients on a DMARD and steroids may not mount a typical
febrile response; therefore a thorough clinical examination is necessary, including
a thorough joint examination in which joint pain might be the most significant sign of
infection.20
The ACR recommends routine tuberculosis (TB) screening for all patients who are
being considered for treatment with biologic DMARDs. This recommendation is based
on the evidence of higher incidence of TB cases following the initiation of anti-TNFa
therapy. All patients should be asked about their risk factors for TB. A negative TB
skin test should not be considered an exclusion of latent TB infection because
many RA patients are immunosuppressed. In cases of active or latent TB, antiTNFa therapy can be started about 1 month after initiating anti-TB therapy with
isoniazid.16
Contraindications to DMARD use include active bacterial infection requiring antibiotic therapy, active TB (untreated), active herpes zoster infection, RA-associated
pneumonitis, or active life-threatening fungal infections. In addition, the ACR recommends against the use of biologic agents during a severe bacterial or viral upper respiratory infection. Each DMARD has its own monitoring requirements and
contraindications that are discussed elsewhere.
Safety ratings vary for use of RA therapies during pregnancy. Methotrexate and
leflunomide have been issued a safety rating X by the Food and Drug Administration.
Safety ratings for other treatments include B for sulfasalazine, C or D for other nonbiologic DMARDs, and B or C for biologic DMARDS.
Several novel therapies have also been studied for RA. Statins (atorvastatin and pravastatin) may have anti-inflammatory properties in the synovium, with an ability to
inhibit both the production and actions of CRP.21 Other novel therapies that are being
studied for the treatment of RA include hematopoietic stem cell transplantation and

Diagnosis and Treatment of Rheumatoid Arthritis

immunoadsorption.21 Lastly, nonpharmacologic therapies must also be considered in

RA treatment. These treatments include physical therapy, occupational therapy,
patient education, and nutrition guidance.22 Moreover, access to a multidisciplinary
team is the best approach to improve symptoms, functional outcomes, and reduce
the progress of disease in patients with RA.15
SUMMARY

RA is an autoimmune disease that is characterized by synovitis, which eventually

causes destruction of cartilage and bone. The pathogenesis is still being elucidated
by ongoing research, but is generally described by a complicated interaction of
genetics and arthrogenic antigens in the environment that interact to precipitate an
inflammatory cascade, leading to bone and joint destruction. The course of the
disease is unpredictable and usually varies among those who are afflicted.23 No single
laboratory test or physical finding can diagnose RA because it is largely a clinical diagnosis. However, laboratory tests and radiologic findings when combined with the
physical examination can help to increase diagnostic accuracy. Primary care physicians should include screening questions during routine visits to increase the early
detection of RA. Patients who are diagnosed with RA by primary care physicians
should be referred to a rheumatologist expeditiously to limit disease progression as
well as to minimize the extra-articular disease involvement. If untreated, the great
majority of these patients become disabled.3 The recent development of DMARDs
has had a positive impact on disease progression and patient outcomes. Conversely,
their use can be complicated by the development of adverse reactions, which always
have the potential to complicate the symptoms of disease. The onset of RA can occur
at any point in the life span, so that attention to the history and physical examination is
the best means of uncovering this potentially aggressive disease. Nonpharmacologic
therapies are also an important component of treatment.
There remain several issues that primarily limit our ability to provide optimal treatment. Access to many therapies continues to be limited by formulary restrictions,
the costs of the DMARDs, prior authorization requirements by private insurers (which
often include the requirement for inadequate responses to multiple DMARD treatments), and further limitation of the more expensive DMARD therapies to individuals
with the most severe and longest duration of disease.23 Overcoming the barriers to
optimal treatment requires the growth of awareness that the disabling and life-threatening elements of RA are comparable with those of many other diseases.23 Despite
the remarkable progress made in delineating the pathogenesis of RA, as well as the
development of disease-modifying treatment modalities, many questions remain
unanswered and the cure remains elusive.
REFERENCES

1. Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am

Fam Physician 2005;72(6):103747.
2. Kountz D, Von Feldt JM. Management of rheumatoid arthritis: a primary care
perspective. J Fam Pract 2007;56(10A):59a71a.
3. Weinblatt ME, Kuritzky L. Rheumatoid arthritis. J Fam Pract 2007;56(4):S17.
4. CDC. Rheumatoid arthritis. Diseases and conditions 2009. October 28. Available at:
http://www.cdc.gov/arthritis/basics/rheumatoid.htm; 2009. Accessed November 5,
2009.
5. Costenbader KH, Kountz DS. Treatment and management of early RA: a primary
care primer. J Fam Pract 2007;56(7 Suppl):S17 [quiz: S8].

791

792

Birch & Bhattacharya

6. Arend WP. The pathophysiology and treatment of rheumatoid arthritis. Arthritis

Rheum 1997;40(4):5957.
7. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association
1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum
1988;31(3):31524.
8. ARUP. Rheumatoid arthritis. The physicians guide to laboratory test selection and
interpretation 2009. Available at: http://www.arupconsult.com/Topics/RA.html.
August 2009. Accessed November 5, 2009.
9. Heidari B, Abedi H, Firouzjahi A, et al. Diagnostic value of synovial fluid anticyclic citrullinated peptide antibody for rheumatoid arthritis. Rheumatol Int
October 13, 2009. [online].
10. Samanci N, Ozdem S, Akbas H, et al. Diagnostic value and clinical significance
of anti-CCP in patients with advanced rheumatoid arthritis. J Natl Med Assoc
2005;97(8):11206.
11. Firestein GS, Panayi GS, Wollheim FA. Rheumatoid arthritis: frontiers in pathogenesis and treatment. New York: Oxford University Press; 2000.
12. Schaller JG. Juvenile rheumatoid arthritis. Pediatr Rev 1997;18(10):33749.
13. CDC. Centers for Disease Control and Prevention. Childhood arthritis. 2009.
Available at: http://www.cdc.gov/arthritis/basics/childhood.htm. Accessed
December 2, 2009.
14. Villa-Blanco JI, Calvo-Alen J. Elderly onset rheumatoid arthritis: differential diagnosis and choice of first-line and subsequent therapy. Drugs Aging 2009;26(9):
73950.
15. National Guideline Clearinghouse. Rheumatoid Arthritis. The management of rheumatoid arthritis in adults. 2003 November (revised 2009 February). NGC:007178.
Available at: www.guideline.gov. Accessed October 15, 2009.
16. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008
recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59(6):76284.
17. Silverstein F, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib
vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis:
the CLASS study: a randomized controlled trial. Celecoxib long-term arthritis
safety study. JAMA 2000;284(10):124755.
18. Lo V, Meadows SE, Saseen J. When should COX-2 selective NSAIDs be used for
osteoarthritis and rheumatoid arthritis? J Fam Pract 2006;55(3):2602.
19. Hodgson SF, Watts NB, Bilezikian JP, et al, AACE Osteoporosis Task Force. American Association of Clinical Endocrinologists medical guidelines for the clinical
practice for the prevention and treatment of postmenopausal osteoporosis. Endocr Pract 2003;9(6):54464.
20. Bingham CO 3rd, Miner MM. Treatment, management, and monitoring of established rheumatoid arthritis. J Fam Pract 2007;56(Suppl Rapid 10):S17 [quiz: S8].
21. Harris E. Miscellaneous novel therapies in rheumatoid arthritis. Waltham (MA):
UpToDate, Inc; 2009.
22. Harris E. Nonpharmacologic and preventive therapies of rheumatoid arthritis.
Waltham (MA): UpToDate, Inc; 2009.
23. Bykerk V. Unmet needs in rheumatoid arthritis. J Rheumatol Suppl 2009;82:426.